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Toxicology Rounds: The Ironic, Neurotic Methylene Blue

Gussow, Leon MD

doi: 10.1097/01.EEM.0000394583.88495.71
Toxicology Rounds
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Methylene blue is a relatively old antidote, first used to treat aniline-induced methemoglobinemia in 1933. Yet many clinicians still do not fully understand how it works, or, for that matter, why it sometimes doesn't. Despite its long use, methylene blue has important adverse drug interactions that only recently came to light. Clinicians should keep three key concepts in mind when using this fascinating antidote.

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Key Concept 1.

Methylene blue is an oxidizing agent. The goal when treating methemoglobinemia is to reduce methemoglobin (that has some iron in the ferric Fe+3 state) to normal hemoglobin with ferrous Fe+2 iron. Ferric iron is not capable of carrying oxygen; its presence decreases oxygen supply to the tissues, and produces a functional anemia.

Because of some inefficiency in the normal process of carrying and releasing oxygen, a small amount of methemoglobin is continually being formed even in healthy individuals. Biochemical pathways primarily involving NADH and NADH-dependent methemoglobin reductase keep normal methemoglobin levels at or under 1%. A second, usually minor, pathway involves NADPH. When methemoglobin levels increase, often because of exposure to any of a large number of different drugs or chemicals (nitrates/nitrites, chlorate, nitroglycerin, and primaquine, among others), the NADH pathway becomes saturated. Unfortunately, lack of an electron donor limits the capacity of the minor NADPH route to become more active and prevent methemoglobin levels from increasing.

It is often noted that the action of methylene blue is paradoxical: To treat cyanotic (blue) patients with methemoglobinemia, we administer a blue antidote. But it is also paradoxical that we give an oxidizing agent to reduce ferric methemoglobin. This works because in the presence of sufficient NADPH, methylene blue is reduced to leukomethylene blue that then serves as an electron donor in the conversion of methemoglobin to hemoglobin. This increases the activity of the minor NADPH pathway many times over, rapidly decreasing the methemoglobin level.

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Key Concept 2.

The enzyme glucose 6-phosphate dehydrogenase (G6PD) is a key enzyme in generating NADPH. Patients with G6PD deficiency have reduced the amount of NADPH present, and are not able to reduce methylene blue to leukomethylene blue. When methylene blue is administered, high levels build up and oxidize additional hemoglobin ferrous iron to the ferric state, increasing methemoglobin levels. If a patient fails to respond after methylene blue is given or actually gets worse and has increasing methemoglobin levels, G6PD deficiency should be suspected and further administration of the antidote avoided. There are several other conditions that can cause a similar lack of response. (See table.) High doses of methylene blue also can increase methemoglobin levels. The usual recommended dose is 1-2 mg/kg of a 1% solution given over five minutes. This can be repeated if needed, but the total dose generally should not exceed 7 mg/kg.

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Key Concept 3.

Methylene blue is a monoamine oxidase inhibitor (MAOI), and has antidepressant properties. This concept is relatively new, and developed from case reports of post-surgical delirium in patients given methylene blue prior to parathyroidectomy. (The dye makes it easier for surgeons to identify and delineate the gland.) When these cases were analyzed, it became apparent that all affected patients were taking or had recently been taking a selective serotonin-reuptake inhibitor (SSRI). In addition, they all had other signs consistent with severe serotonin toxicity: agitation, tremor, muscle rigidity, increased reflexes, clonus, and autonomic hyperactivity (diaphoresis, hyperthermia, tachycardia). Patients given methylene blue who had not been exposed to SSRIs did not seem to develop these manifestations.

Because severe serotonin toxicity is caused by an interaction of an SRI and a MAOI and not by an SSRI alone even in overdose, researchers suspected that methylene blue must have MAOI properties. It has now been demonstrated conclusively in vitro and in animal models that methylene blue is indeed a potent inhibitor of MAO-A. In fact, methylene blue has been shown effective in treating animal models of depression. The pharmacology of methylene blue and its role in producing severe serotonin toxicity has been reviewed in an important recent article. (J Psychopharmacol 2010;24[10]:1433.)

To my knowledge, there have been no reported cases of severe serotonin toxicity associated with the use of methylene blue as an antidote to methemoglobinemia. This may be explained by the fact that doses in this situation are considerably lower than those used in surgery. Even a low dose (1 mg/kg), however, will produce serum and CNS levels theoretically sufficient to inhibit MAO-A.

By the way, other drugs that unexpectedly act as MAOIs include the tricyclic antidepressant clomipramine and the antibiotic linezolid.

I've always thought methylene blue to be the most ironic and most interesting of all antidotes. It is conflicted and neurotic, always threatening to get in its own way, to work at cross-purposes, and to bring about an outcome exactly opposite to the one intended. As noted before, it is a blue dye administered to a blue (cyanotic) patient to restore normal skin color. It is an oxidizing agent given to reverse abnormal oxidation of the iron in hemoglobin. And it is a blue drug effective in treating the blues (depression), at least in animals. When one thinks of methylene blue, it indeed seems there are too many ironies in the fire.

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Reasons for Failure to Respond to Methylene Blue

  • G6PD deficiency
  • Sulfhemoglobinemia
  • Continuing drug absorption
  • NADPH methemoglobin reductase deficiency
  • High doses of methylene blue (usually > 7 mg/kg)

Source: Clinical Toxicology. Philadelphia: W.B. Saunders Company; 2001.

Dr. Gussow

Dr. Gussow

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